Publications by authors named "Françoise Bergametti"

17 Publications

  • Page 1 of 1

End-truncated LAMB1 causes a hippocampal memory defect and a leukoencephalopathy.

Ann Neurol 2021 Oct 4. Epub 2021 Oct 4.

Université de Paris, INSERM UMR 1141 NeuroDiderot, F-75019, Paris, France.

Objective: The majority of patients with a familial cerebral small vessel disease (CSVD) referred for molecular screening do not show pathogenic variants in known genes. In this study, we aimed to identify novel CSVD causal genes.

Methods: We performed a gene-based collapsing test of rare protein truncating variants identified in exome data of 258 unrelated CSVD patients of an ethnically matched control cohort and of two publicly available large-scale databases, gnomAD and TOPMed. Western blotting was used to investigate variants functional consequences. Clinical and MRI features of mutated patients were characterized.

Results: We showed that LAMB1 truncating variants escaping nonsense-mediated mRNA decay are strongly overrepresented in CSVD patients, reaching genome-wide significance (p < 5 x10 ). Using two antibodies recognizing the N-and C-terminal parts of LAMB1, we showed that truncated forms of LAMB1 are expressed in patients' endogenous fibroblasts and are trapped in the cytosol. These variants are associated with a novel phenotype characterized by the association of a hippocampal type episodic memory defect and a diffuse vascular leukoencephalopathy.

Interpretation: These findings are important for diagnosis and clinical care, to avoid unnecessary and sometimes invasive investigations, and also from a mechanistic point of view to understand the role of extracellular matrix proteins in neuronal homeostasis. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/ana.26242DOI Listing
October 2021

Heterozygous HTRA1 nonsense or frameshift mutations are pathogenic.

Brain 2021 Jul 16. Epub 2021 Jul 16.

AP-HP, Service de Génétique Moléculaire Neurovasculaire, Hôpital Saint-Louis, France.

Heterozygous missense HTRA1 mutations have been associated with an autosomal dominant cerebral small vessel disease whereas the pathogenicity of heterozygous HTRA1 stop codon variants is unclear. We performed a targeted high throughput sequencing of all known cerebral small vessel disease genes, including HTRA1, in 3,853 unrelated consecutive CSVD patients referred for molecular diagnosis. The frequency of heterozygous HTRA1 mutations leading to a premature stop codon in this patient cohort was compared with their frequency in large control databases. An analysis of HTRA1 messenger RNA was performed in several stop codon carrier patients. Clinical and neuroimaging features were characterized in all probands. Twenty unrelated patients carrying a heterozygous HTRA1 variant leading to a premature stop codon were identified. A highly significant difference was observed when comparing our patient cohort with control databases (gnomAD v3.1.1 (p = 3.12 x 10-17, OR = 21.9), TOPMed freeze 5 (p = 7.6 x 10-18, OR = 27.1) and 1000 Genomes (p = 1.5 x 10-5). Messenger RNA analysis performed in eight patients showed a degradation of the mutated allele strongly suggesting a haploinsufficiency. Clinical and neuroimaging features are similar to those previously reported in heterozygous missense mutation carriers, except for penetrance, which seems lower. Altogether, our findings strongly suggest that heterozygous HTRA1 stop codons are pathogenic through a haploinsufficiency mechanism. Future work will help to estimate their penetrance, an important information for genetic counseling.
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http://dx.doi.org/10.1093/brain/awab271DOI Listing
July 2021

Novel CCM2 missense variants abrogating the CCM1-CCM2 interaction cause cerebral cavernous malformations.

J Med Genet 2020 06 14;57(6):400-404. Epub 2020 Jan 14.

UMR-S1141, INSERM, Paris, Île-de-France, France

Background: Cerebral cavernous malformations (CCMs) are vascular malformations mostly located within the central nervous system. Most deleterious variants are loss of function mutations in one of the three genes. These genes code for proteins that form a ternary cytosolic complex with CCM2 as a hub. Very few missense variants have been shown to be deleterious by modifying the ternary CCM complex stability.

Objectives: To investigate the causality of novel missense variants detected in patients with CCM.

Methods: The three CCM genes were screened in 984 patients referred for molecular screening. Interaction between CCM1 and CCM2 proteins was tested using co-immunoprecipitation experiments for the missense variants located in the phosphotyrosine binding (PTB) domain.

Results: 11 distinct rare missense variants were found. Six variants predicted to be damaging were located in the PTB domain, four of them were novel. When co-transfected with CCM1 in HEK293T cells, a loss of interaction between CCM1 and CCM2 was observed for all six variants.

Conclusion: We showed, using co-immunoprecipitation experiments, that CCM2 missense variants located in the PTB domain were actually damaging by preventing the normal interaction between CCM1 and CCM2. These data are important for diagnosis and genetic counselling, which are challenging in patients harbouring such variants.
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http://dx.doi.org/10.1136/jmedgenet-2019-106401DOI Listing
June 2020

The pleiotropy associated with de novo variants in CHD4, CNOT3, and SETD5 extends to moyamoya angiopathy.

Genet Med 2020 02 2;22(2):427-431. Epub 2019 Sep 2.

Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA.

Purpose: Moyamoya angiopathy (MMA) is a cerebrovascular disease characterized by occlusion of large arteries, which leads to strokes starting in childhood. Twelve altered genes predispose to MMA but the majority of cases of European descent do not have an identified genetic trigger.

Methods: Exome sequencing from 39 trios were analyzed.

Results: We identified four de novo variants in three genes not previously associated with MMA: CHD4, CNOT3, and SETD5. Identification of additional rare variants in these genes in 158 unrelated MMA probands provided further support that rare pathogenic variants in CHD4 and CNOT3 predispose to MMA. Previous studies identified de novo variants in these genes in children with developmental disorders (DD), intellectual disability, and congenital heart disease.

Conclusion: These genes encode proteins involved in chromatin remodeling, and taken together with previously reported genes leading to MMA-like cerebrovascular occlusive disease (YY1AP1, SMARCAL1), implicate disrupted chromatin remodeling as a molecular pathway predisposing to early onset, large artery occlusive cerebrovascular disease. Furthermore, these data expand the spectrum of phenotypic pleiotropy due to alterations of CHD4, CNOT3, and SETD5 beyond DD to later onset disease in the cerebrovascular arteries and emphasize the need to assess clinical complications into adulthood for genes associated with DD.
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http://dx.doi.org/10.1038/s41436-019-0639-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673309PMC
February 2020

Clinical and Molecular Features of 5 European Multigenerational Families With Moyamoya Angiopathy.

Stroke 2019 04;50(4):789-796

Department of Neurology, Alfried Krupp Hospital Essen, Germany (J.C.S., M.K.).

Background and Purpose Moyamoya angiopathy (MMA) is a rare cerebral vasculopathy outside of Asia. In Japanese patients, a vast majority of patients carry the founder p.R4810K variant in the RNF213 gene, and familial cases are around 10%. In European patients, data about familial occurrence are limited. The aim of this study was to characterize the clinical and molecular features of several European families with a parent-to-child transmission of MMA. Methods Out of 126 MMA probands referred, we identified 113 sporadic probands and 13 familial probands. Segregation analysis showed a vertical parent-to-child pattern of inheritance in the families of 5 of these probands. All 5 families were of German or Dutch ancestry. We investigated the clinical features of affected members and used whole-exome sequencing to screen RNF213 and 13 genes involved in Mendelian MMA and to identify genes recurrently mutated in these families. Results Twelve affected MMA patients were identified, including 9 females and 3 males. Age at clinical onset ranged from 11 to 65 years. In 3 of 5 families, associated livedo racemosa was found. We did not detect any deleterious variants in the 13 known MMA genes. RNF213 rare missense variants predicted to be pathogenic were detected in all affected members of 2 of these families, as well as 2 candidate variants of the PALD1 gene. Conclusions Nonsyndromic MMA was identified in 5 European families, including 2 to 3 clinically affected cases segregating with a parent-to-child pattern of inheritance in each family. Molecular screening detected rare deleterious variants within RNF213 and PALD1 in all affected members of 2 of these 5 families, as well as in some clinically unaffected members. Altogether these data raise the difficult and, to date unanswered, question of the medical indication of presymptomatic screening.
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http://dx.doi.org/10.1161/STROKEAHA.118.023972DOI Listing
April 2019

Rare RNF213 variants in the C-terminal region encompassing the RING-finger domain are associated with moyamoya angiopathy in Caucasians.

Eur J Hum Genet 2017 08 21;25(8):995-1003. Epub 2017 Jun 21.

Inserm UMR-S1161, Génétique et Physiopathologie des Maladies Cérébro-vasculaires, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.

Moyamoya angiopathy (MMA) is a cerebral angiopathy affecting the terminal part of internal carotid arteries. Its prevalence is 10 times higher in Japan and Korea than in Europe. In East Asian countries, moyamoya is strongly associated to the R4810K variant in the RNF213 gene that encodes for a protein containing a RING-finger and two AAA+ domains. This variant has never been detected in Caucasian MMA patients, but several rare RNF213 variants have been reported in Caucasian cases. Using a collapsing test based on exome data from 68 European MMA probands and 573 ethnically matched controls, we showed a significant association between rare missense RNF213 variants and MMA in European patients (odds ratio (OR)=2.24, 95% confidence interval (CI)=(1.19-4.11), P=0.01). Variants specific to cases had higher pathogenicity predictive scores (median of 24.2 in cases versus 9.4 in controls, P=0.029) and preferentially clustered in a C-terminal hotspot encompassing the RING-finger domain of RNF213 (P<10). This association was even stronger when restricting the analysis to childhood-onset and familial cases (OR=4.54, 95% CI=(1.80-11.34), P=1.1 × 10). All clinically affected relatives who were genotyped were carriers. However, the need for additional factors to develop MMA is strongly suggested by the fact that only 25% of mutation carrier relatives were clinically affected.
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http://dx.doi.org/10.1038/ejhg.2017.92DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5567158PMC
August 2017

De novo mutations in CBL causing early-onset paediatric moyamoya angiopathy.

J Med Genet 2017 08 25;54(8):550-557. Epub 2017 Mar 25.

French Center for Pediatric Stroke, University Hospital Necker-Enfants malades, Paris, France.

Background: Moyamoya angiopathy (MMA) is characterised by a progressive stenosis of the terminal part of the internal carotid arteries and the development of abnormal collateral deep vessels. Its pathophysiology is unknown. MMA can be the sole manifestation of the disease (moyamoya disease) or be associated with various conditions (moyamoya syndrome) including some Mendelian diseases. We aimed to investigate the genetic basis of moyamoya using a whole exome sequencing (WES) approach conducted in sporadic cases without any overt symptom suggestive of a known Mendelian moyamoya syndrome.

Methods: A WES was performed in four unrelated early-onset moyamoya sporadic cases and their parents (trios). Exome data were analysed under dominant de novo, autosomal recessive and X-linked hypotheses. A panel of 17 additional sporadic cases with early-onset moyamoya was available for mutation recurrence analysis.

Results: We identified two germline de novo mutations in in two out of the four trio probands, two girls presenting with an infancy-onset severe MMA. Both mutations were predicted to alter the ubiquitin ligase activity of the CBL protein that acts as a negative regulator of the RAS pathway. These two germline mutations have previously been described in association with a developmental Noonan-like syndrome and susceptibility to juvenile myelomonocytic leukaemia (JMML). Notably, the two mutated girls never developed JMML and presented only subtle signs of RASopathy that did not lead to evoke this diagnosis during follow-up.

Conclusions: These data suggest that gene screening should be considered in early-onset moyamoya, even in the absence of obvious signs of RASopathy.
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http://dx.doi.org/10.1136/jmedgenet-2016-104432DOI Listing
August 2017

Disruption of a miR-29 binding site leading to COL4A1 upregulation causes pontine autosomal dominant microangiopathy with leukoencephalopathy.

Ann Neurol 2016 Nov 19;80(5):741-753. Epub 2016 Oct 19.

Inserm U1161, Genetics and Physiopathology of Cerebrovascular Diseases, Paris, France.

Objective: Cerebral small vessel disease (cSVD) is a heterogeneous group of disorders. Screening of known cSVD genes identifies the causative mutation in <15% of familial cSVD cases. We sought to identify novel causes of cSVD.

Methods: We used linkage analysis and exome sequencing to identify the causal mutation in a French cSVD family. The identified candidate gene was then screened in 202 cSVD unrelated probands, including 1 proband from the first reported pontine autosomal dominant microangiopathy with leukoencephalopathy (PADMAL) family. Sanger sequencing was used to confirm variants in all mutated probands and analyze their segregation in probands' relatives. Mutation consequences were assessed with luciferase reporter assays and real-time quantitative polymerase chain reaction (RT-qPCR).

Results: A candidate heterozygous variant located in a predicted miR-29 microRNA binding site, within the 3' untranslated region of COL4A1, was identified in the large French cSVD family. Five additional unrelated probands, including the PADMAL proband, harbored heterozygous variants in this microRNA binding site. Variants cosegregated with the affected phenotype, and cumulative logarithm of odds score reached 6.03, establishing linkage to this locus. A highly significant difference was observed when comparing the number of variants within this binding site in cases and controls (p = 1.77 × 10E-12). RT-qPCR analyses of patients' primary fibroblasts and luciferase reporter assays strongly favor an upregulation of COL4A1 mediated by disruption of miR-29 binding to its target site. Magnetic resonance imaging features were characterized by the presence of multiple pontine infarcts in all symptomatic mutation carriers.

Interpretation: Mutations upregulating COL4A1 expression lead to PADMAL, a severe early onset ischemic cSVD, distinct from the various phenotypes associated with COL4A1 missense glycine mutations. Ann Neurol 2016;80:741-753.
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http://dx.doi.org/10.1002/ana.24782DOI Listing
November 2016

Can whole-exome sequencing data be used for linkage analysis?

Eur J Hum Genet 2016 Apr 15;24(4):581-6. Epub 2015 Jul 15.

INSERM, UMR 1161, Paris, France.

Whole-exome sequencing (WES) has become the strategy of choice to identify causal variants in monogenic disorders. However, the list of candidate variants can be quite large, including false positives generated by sequencing errors. To reduce this list of candidate variants to the most relevant ones, a cost-effective strategy would be to focus on regions of linkage identified through linkage analysis conducted with common polymorphisms present in WES data. However, the non-uniform exon coverage of the genome and the lack of knowledge on the power of this strategy have largely precluded its use so far. To compare the performance of linkage analysis conducted with WES and SNP chip data in different situations, we performed simulations on two pedigree structures with, respectively, a dominant and a recessive trait segregating. We found that the performance of the two sets of markers at excluding regions of the genome were very similar, and there was no real gain at using SNP chip data compared with using the common SNPs extracted from WES data. When analyzing the real WES data available for these two pedigrees, we found that the linkage information derived from the WES common polymorphisms was able to reduce by half the list of candidate variants identified by a simple filtering approach. Conducting linkage analysis with WES data available on pedigrees and excluding among the candidate variants those that fall in excluded linkage regions is thus a powerful and cost-effective strategy to reduce the number of false-positive candidate variants.
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http://dx.doi.org/10.1038/ejhg.2015.143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4929867PMC
April 2016

Heterozygous HTRA1 mutations are associated with autosomal dominant cerebral small vessel disease.

Brain 2015 Aug 10;138(Pt 8):2347-58. Epub 2015 Jun 10.

1 INSERM UMR 1161, Génétique et Physiopathologie des Maladies Cérébro-vasculaires, Paris, France 2 Université Paris Diderot, Sorbonne Paris Cité, UMR-S1161, Paris, France 5 AP-HP, Groupe Hospitalier Saint-Louis Lariboisière-Fernand-Widal, Service de Génétique Moléculaire Neurovasculaire, Centre de Référence des Maladies Vasculaires Rares du Cerveau et de l'Oeil (CERVCO), Paris, France

Cerebral small vessel disease represents a heterogeneous group of disorders leading to stroke and cognitive impairment. While most small vessel diseases appear sporadic and related to age and hypertension, several early-onset monogenic forms have also been reported. However, only a minority of patients with familial small vessel disease carry mutations in one of known small vessel disease genes. We used whole exome sequencing to identify candidate genes in an autosomal dominant small vessel disease family in which known small vessel disease genes had been excluded, and subsequently screened all candidate genes in 201 unrelated probands with a familial small vessel disease of unknown aetiology, using high throughput multiplex polymerase chain reaction and next generation sequencing. A heterozygous HTRA1 variant (R166L), absent from 1000 Genomes and Exome Variant Server databases and predicted to be deleterious by in silico tools, was identified in all affected members of the index family. Ten probands of 201 additional unrelated and affected probands (4.97%) harboured a heterozygous HTRA1 mutation predicted to be damaging. There was a highly significant difference in the number of likely deleterious variants in cases compared to controls (P = 4.2 × 10(-6); odds ratio = 15.4; 95% confidence interval = 4.9-45.5), strongly suggesting causality. Seven of these variants were located within or close to the HTRA1 protease domain, three were in the N-terminal domain of unknown function and one in the C-terminal PDZ domain. In vitro activity analysis of HTRA1 mutants demonstrated a loss of function effect. Clinical features of this autosomal dominant small vessel disease differ from those of CARASIL and CADASIL by a later age of onset and the absence of the typical extraneurological features of CARASIL. They are similar to those of sporadic small vessel disease, except for their familial nature. Our data demonstrate that heterozygous HTRA1 mutations are an important cause of familial small vessel disease, and that screening of HTRA1 should be considered in all patients with a hereditary small vessel disease of unknown aetiology.
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http://dx.doi.org/10.1093/brain/awv155DOI Listing
August 2015

Cerebral cavernous malformations arise independent of the heart of glass receptor.

Stroke 2014 May 18;45(5):1505-1509. Epub 2014 Mar 18.

Department of Medicine and Cardiovascular Institute, University of Pennsylvania, 421 Curie Blvd, Philadelphia PA 1910.

Background And Purpose: The Heart of Glass (HEG) receptor binds KRIT1 and functions with KRIT1, CCM2, and PDCD10 in a common signaling pathway required for heart and vascular development. Mutations in KRIT1, CCM2, and PDCD10 also underlie human cerebral cavernous malformation (CCM) and postnatal loss of these genes in the mouse endothelium results in rapid CCM formation. Here, we test the role of HEG in CCM formation in mice and in humans.

Methods: We constitutively or conditionally deleted Heg and Ccm2 genes in genetically modified mice. Mouse embryos, brain, and retina tissues were analyzed to assess CCM lesion formation.

Results: In postnatal mice, CCMs form with Ccm2-/- but not with Heg-/- or Heg-/-;Ccm2+/- endothelial cells. Consistent with these findings, human patients with CCM who lack exonic mutations in KRIT1, CCM2, or PDCD10 do not have mutations in HEG.

Conclusions: These findings suggest that the HEG-CCM signaling functions during cardiovascular development and growth, whereas CCMs arise because of loss of HEG-independent CCM signaling in the endothelium of the central nervous system after birth.
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http://dx.doi.org/10.1161/STROKEAHA.114.004809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4006321PMC
May 2014

Loss of α1β1 soluble guanylate cyclase, the major nitric oxide receptor, leads to moyamoya and achalasia.

Am J Hum Genet 2014 Mar 27;94(3):385-94. Epub 2014 Feb 27.

Institut National de la Santé et de la Recherche Médicale U1161, 75010 Paris, France; UMR-S1161, Génétique des Maladies Vasculaires, Université Paris Diderot, Sorbonne Paris Cité, 75010 Paris, France; Service de Génétique Moléculaire Neurovasculaire, Centre de Référence des Maladies Vasculaires Rares du Cerveau et de l'Oeil, Groupe Hospitalier Saint-Louis Lariboisière-Fernand-Widal, Assistance Publique - Hôpitaux de Paris, 75010 Paris, France. Electronic address:

Moyamoya is a cerebrovascular condition characterized by a progressive stenosis of the terminal part of the internal carotid arteries (ICAs) and the compensatory development of abnormal "moyamoya" vessels. The pathophysiological mechanisms of this condition, which leads to ischemic and hemorrhagic stroke, remain unknown. It can occur as an isolated cerebral angiopathy (so-called moyamoya disease) or in association with various conditions (moyamoya syndromes). Here, we describe an autosomal-recessive disease leading to severe moyamoya and early-onset achalasia in three unrelated families. This syndrome is associated in all three families with homozygous mutations in GUCY1A3, which encodes the α1 subunit of soluble guanylate cyclase (sGC), the major receptor for nitric oxide (NO). Platelet analysis showed a complete loss of the soluble α1β1 guanylate cyclase and showed an unexpected stimulatory role of sGC within platelets. The NO-sGC-cGMP pathway is a major pathway controlling vascular smooth-muscle relaxation, vascular tone, and vascular remodeling. Our data suggest that alterations of this pathway might lead to an abnormal vascular-remodeling process in sensitive vascular areas such as ICA bifurcations. These data provide treatment options for affected individuals and strongly suggest that investigation of GUCY1A3 and other members of the NO-sGC-cGMP pathway is warranted in both isolated early-onset achalasia and nonsyndromic moyamoya.
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http://dx.doi.org/10.1016/j.ajhg.2014.01.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3951937PMC
March 2014

Loss of BRCC3 deubiquitinating enzyme leads to abnormal angiogenesis and is associated with syndromic moyamoya.

Am J Hum Genet 2011 Jun 19;88(6):718-728. Epub 2011 May 19.

INSERM UMR-S-740; Université Paris, 7 Denis Diderot, 10 Avenue de Verdun, 75010 Paris, France; Assistance Publique des Hôpitaux de Paris, Groupe Hospitalier Lariboisière-Saint-Louis, Laboratoire de Génétique, Centre de Référence des Maladies Vasculaires Rares du Cerveau et de l'Oeil, F-75010 Paris, France. Electronic address:

Moyamoya is a cerebrovascular angiopathy characterized by a progressive stenosis of the terminal part of the intracranial carotid arteries and the compensatory development of abnormal and fragile collateral vessels, also called moyamoya vessels, leading to ischemic and hemorrhagic stroke. Moyamoya angiopathy can either be the sole manifestation of the disease (moyamoya disease) or be associated with various conditions, including neurofibromatosis, Down syndrome, TAAD (autosomal-dominant thoracic aortic aneurysm), and radiotherapy of head tumors (moyamoya syndromes). Its prevalence is ten times higher in Japan than in Europe, and an estimated 6%-12% of moyamoya disease is familial in Japan. The pathophysiological mechanisms of this condition remain obscure. Here, we report on three unrelated families affected with an X-linked moyamoya syndrome characterized by the association of a moyamoya angiopathy, short stature, and a stereotyped facial dysmorphism. Other symptoms include an hypergonadotropic hypogonadism, hypertension, dilated cardiomyopathy, premature coronary heart disease, premature hair graying, and early bilateral acquired cataract. We show that this syndromic moyamoya is caused by Xq28 deletions removing MTCP1/MTCP1NB and BRCC3. We also show that brcc3 morphant zebrafish display angiogenesis defects that are rescued by endothelium-specific expression of brcc3. Altogether, these data strongly suggest that BRCC3, a deubiquitinating enzyme that is part of the cellular BRCA1 and BRISC complexes, is an important player in angiogenesis and that BRCC3 loss-of-function mutations are associated with moyamoya angiopathy.
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http://dx.doi.org/10.1016/j.ajhg.2011.04.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3113251PMC
June 2011

Recent insights into cerebral cavernous malformations: the molecular genetics of CCM.

FEBS J 2010 Mar 22;277(5):1070-5. Epub 2010 Jan 22.

AP-HP, Hôpital Lariboisière, Laboratoire de Génétique, Paris, France.

Cerebral cavernous malformations (CCM) are vascular lesions which can occur as a sporadic (80% of the cases) or familial autosomal dominant form (20%). Three CCM genes have been identified: CCM1/KRIT1, CCM2/MGC4607 and CCM3/PDCD10. Almost 80% of CCM patients affected with a genetic form of the disease harbor a heterozygous germline mutation in one of these three genes. Recent work has shown that a two-hit mechanism is involved in CCM pathogenesis which is caused by a complete loss of any of the three CCM proteins within endothelial cells lining the cavernous capillary cavities. These data were an important step towards the elucidation of the mechanisms of this condition.
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http://dx.doi.org/10.1111/j.1742-4658.2009.07535.xDOI Listing
March 2010

Genetics of cavernous angiomas.

Lancet Neurol 2007 Mar;6(3):237-44

INSERM, U740, Paris, France.

Cerebral cavernous malformations (CCM) are vascular malformations that can occur as a sporadic or a familial autosomal dominant disorder. Clinical and cerebral MRI data on large series of patients with a genetic form of the disease are now available. In addition, three CCM genes have been identified: CCM1/KRIT1, CCM2/MGC4607, and CCM3/PDCD10. These recent developments in clinical and molecular genetics have given us useful information about clinical care and genetic counselling and have broadened our understanding of the mechanisms of this disorder.
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http://dx.doi.org/10.1016/S1474-4422(07)70053-4DOI Listing
March 2007

Genotype-phenotype correlations in cerebral cavernous malformations patients.

Ann Neurol 2006 Nov;60(5):550-6

Institut National de la Sante et de la Recherche Médicale U740, Faculté de Médecine Lariboisière, Paris, France.

Objective: To compare clinical features of CCM1, CCM2, and CCM3 mutation carriers.

Methods: A detailed clinical and molecular analysis of 163 consecutive cerebral cavernous malformation (CCM) families was performed.

Results: A deleterious mutation was detected in 128 probands. Three hundred thirty-three mutation carriers were identified (238 CCM1, 67 CCM2, and 28 CCM3). Ninety-four percent of the probands with an affected relative had a mutation compared with 57% of the probands with multiple lesions but no affected relative (p < 0.001). The number of affected individuals per family was lower in CCM3 families (p < 0.05). The proportion of patients with onset of symptoms before 15 years of age was higher in the CCM3 group (p < 0.0025). Cerebral hemorrhage was the most common initial presentation in CCM3 patients. The average number of T2-weighted imaging lesions was similar in the three groups, in contrast with a significantly lower number of gradient-echo sequence lesions in CCM2 patients (p < 0.05). The number of gradient-echo sequence lesions increased more rapidly with age in CCM1 than in CCM2 patients (p < 0.05).

Interpretation: Despite similarities among the three groups, there is a significantly lower number of affected individuals in CCM3 pedigrees, CCM3 mutations may confer a higher risk for cerebral hemorrhage, particularly during childhood, and the increment of gradient-echo sequence lesions with age differs between CCM1 and CCM2 patients.
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http://dx.doi.org/10.1002/ana.20947DOI Listing
November 2006

Turnover of hepatitis B virus X protein is regulated by damaged DNA-binding complex.

J Virol 2002 Jul;76(13):6495-501

Unité de Recombinaison et Expression Génétique (INSERM U163), Institut Pasteur, 28 rue du Dr Roux, 75724 Paris Cedex 15, France.

Mammalian hepatitis B viruses encode an essential regulatory protein, termed X, which may also be implicated in liver cancer development associated with chronic infection. X protein, also referred to as HBx in human virus and WHx in woodchuck virus, has been reported to bind to a number of cellular proteins, including the DDB1 subunit of the damaged DNA-binding (DDB) complex. Our previous work provided genetic evidence for the importance of WHx-DDB1 interaction in both the activity of the X protein and establishment of viral infection in woodchucks. In the present study, a direct action of DDB1 on the X protein is documented. Physical interaction between the two proteins leads to an increase in X protein stability. This effect results from protection of the viral protein from proteasome-mediated degradation. Protection of WHx is overcome in the presence DDB2, the second subunit of the DDB heterodimer. In keeping with observations reported for HBx, DDB2 was found to directly bind to WHx. Nonetheless, the counteracting effect of DDB2 on X stabilization requires DDB2-DDB1 interaction. Taken together, these findings substantiate the physical and functional connection between the X protein and the DDB1-DDB2 heterodimer, leading to the regulation of the pool of the viral protein.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC136256PMC
http://dx.doi.org/10.1128/jvi.76.13.6495-6501.2002DOI Listing
July 2002
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